The broad, long-term, objectives of this proposal are to sensitivity to excitotoxicity. Stimulation of excitatory amino acid receptors, particularly those of the N-methyl-D-aspartic acid (NMDA) and kainate subtype of glutamate receptor, can trigger delayed neuronal death that occurs over a period of hours to days. This process, commonly referred to as excitotoxicity, is thought to involve excessive and prolonged increases of intracellular calcium that ultimately lead to calcium-induced neuronal death. Recent studies have shown that ethanol has potent inhibitory actions on NMDA and kainate receptor mediated calcium influx. Preliminary data contained in this proposal shows that in primary neuronal cultures, acute in vitro ethanol can potently inhibit NMDA receptor mediated excitotoxicity. The first portion of this proposal (specific aims 1 and 2) consist of in vitro studies using primary rat neuronal cultures that will fully characterize the acute and chronic effects of ethanol on excitotoxicity. Acute studies will examine the effects of ethanol on calcium influx, the role of voltage-dependent calcium channels in excitotoxicity and their interaction with ethanol in this process, and the differential sensitivity of certain neurons to excitotoxicity and to excitoprotection by ethanol. The effects of chronic in vitro ethanol treatment on neuronal cultures, including the ability of chronic ethanol to sensitize neurons to excitotoxicity via upregulation of both excitatory amino acid-operated and voltage-operated calcium channels, will also be examined. The in vitro studies will provide a foundation for the in vivo studies (specific aims 3 and 4) contained in the second portion of this proposal. A rat model of ishemic brain damage is proposed that will allow investigations of the interactions of both acute and chronic ethanol consumption with ischemia induced delayed neuronal death. Excitatory amino acid receptors, ion channels and neuronal cell death will be quantitated by histopathological and autoradiographic analysis of brain sections. The interaction of ethanol with ischemic brain damage could yield important and clinically significant information on the neurotoxic effects of ethanol and the neuropathology of chronic alcohol abuse.